rs4696715

Positions:

• chr4-8609449-A-C
• chr4-8609449-A-G
• chr4-8609449-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001014447.3(CPZ):​c.1227+2024A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 141,712 control chromosomes in the GnomAD database, including 6,272 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (6272 hom., cov: 35)
• Consequence: CPZ NM_001014447.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376

Genes affected

CPZ (HGNC:2333): (carboxypeptidase Z) This gene encodes a member of the metallocarboxypeptidase family. This enzyme displays carboxypeptidase activity towards substrates with basic C-terminal residues. It is most active at neutral pH and is inhibited by active site-directed inhibitors of metallocarboxypeptidases. Alternative splicing in the coding region results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

LOC124900659 (HGNC:):

GPR78 (HGNC:4528): (G protein-coupled receptor 78) The protein encoded by this gene belongs to the G protein-coupled receptor family, which contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. This is an orphan receptor, which displays significant level of constitutive activity. Association analysis shows preliminary evidence for the involvement of this gene in susceptibility to bipolar affective disorder and schizophrenia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.1227+2024A>C		intron_variant		ENST00000360986.9	NP_001014447.2
LOC124900659	XR_007058014.1	n.3729T>G		non_coding_transcript_exon_variant	3/3
CPZ	NM_001014448.3	c.816+2024A>C		intron_variant			NP_001014448.2
CPZ	NM_003652.4	c.1194+2024A>C		intron_variant			NP_003643.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.1227+2024A>C		intron_variant		1	NM_001014447.3	ENSP00000354255	P4

Frequencies

GnomAD3 genomes AF: 0.300 AC: 42548 AN: 141620 Hom.: 6269 Cov.: 35

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.300 AC: 42565 AN: 141712 Hom.: 6272 Cov.: 35 AF XY: 0.297 AC XY: 20640 AN XY: 69560

Gnomad4 AFR AF: 0.300

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.308

Alfa AF: 0.274 Hom.: 2970

Bravo AF: 0.273

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4696715; hg19: chr4-8611176;